Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice.

Abstract

The molecular millennium has bestowed researchers with the essential tools to identify the underlying genetic substrates for thousands of genetic disorders, most of which are rare and follow mendelian inheritance patterns. The genetic bases of potentially lethal and heritable cardiomyopathies and cardiac channelopathies, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), left ventricular noncompaction, arrhythmogenic right ventricular cardiomyopathy (ARVC), long-QT syndrome (LQTS), short-QT syndrome (SQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS), and familial atrial fibrillation, have been identified and are now better understood. Marked genetic heterogeneity and clinical heterogeneity are hallmark features of these disorders, with multiple genes and allelic variants subserving their underlying pathogenic mechanisms. To date, thousands of gene mutations at the single-nucleotide level have been discovered for this group of divergent cardiovascular disorders of the heart. Most mutations represent pathogenic disease-causing mutations only discovered in disease cohorts, whereas others are common or rare genetic polymorphisms identified in disease and in health that may or may not provide the precise pathogenic substrate. Genetic testing for several of these heritable cardiomyopathies and channelopathies has made its transition from discovery through translation, with clinical genetic tests now available commercially. The purpose of the present review is to provide the reader with a foundational understanding of genetic testing in clinical practice. Here, we will present some general principles of genetic testing, the need for careful interpretation of genetic testing results, the importance of genetic counseling, and some points on the ethical, legal, and societal implications of genetic testing. We will conclude by reviewing the state of clinical genetic testing for 4 of the principal cardiomyopathies/channelopathies: HCM, LQTS, CPVT, and BrS. ### Mutation Types in Human Genetic Disease Genes contain an encrypted genetic message for the assembly of polypeptides or proteins that serve the biological function of the cell. Polypeptides or proteins are polymers of linear repeating units …